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More on the Genetics of Scoliosis

Untwist scoliosis by clipping wings of an overactive ladybird
13 April 2016 Hiroshima University

People with scoliosis, a twisting of the spine that can occur as a birth defect or more commonly starts during the teen years, are now closer to a genetic explanation for their condition. An overactive gene, called ladybird homeobox 1 (LBX1), is the start of a genetic chain reaction that causes the spine to grow abnormally. The report from collaborations at Hiroshima University, Kyoto University, RIKEN, and Kanazawa University is the first to demonstrate the functional association of scoliosis with LBX1.

“A genetic test called the ScoliScore AIS Prognostic Test already exists for adolescents recently diagnosed with scoliosis to predict if the curve of the spine will get worse, which can guide treatment decisions. Studies like ours that identify genes important in causing scoliosis can help further develop this current prognostic test into a clinically predictive genetic test to identify scoliosis before symptoms occur,” said Chisa Shukunami, DDS, PhD, Professor in the Department of Molecular Biology and Biochemistry at Hiroshima University.

The Problem

Scoliosis is a polygenetic disease – mutations in multiple genes are responsible and environmental factors may also be relevant. The scientific community already knows one set of molecules, called the Wnt/PCP signaling pathway, is partially responsible for twisting the spine in scoliosis. These new results reveal how the Wnt/PCP pathway becomes problematic and provide insights for restoring normalcy.

Too little activity of the LBX1 gene has no effect on development. However, the research team suspected that too much LBX1 activity might be problematic. The scientists performed genetic experiments using zebrafish, a small freshwater fish common in research labs, to model scoliosis.

Researchers genetically manipulated zebrafish so they had too much LBX1 and then observed how their spines grew. The timing of when too much LBX1 started was important for how the fish’s bodies developed.

Congenital Scoliosis

During embryonic development, groups of cells form a pattern of mirror images on either side of the body and eventually become many different parts of the spine. In embryos injected with extra LBX1, the cells responsible for becoming the backbone and back muscles were wider than in healthy fish. Fish that survived long enough developed misshapen bones in their backs, which caused their scoliosis. Scoliosis in humans is not fatal, but researchers believe this model represents the birth defect version of scoliosis in humans because the bones are obviously misshapen.

Adolescent Idiopathic Scoliosis

Another group of zebrafish were genetically modified to express extra LBX1 throughout their entire lives, but only in some cells, making them what researchers call genetic mosaics. Some of these fish developed bones with the correct shape, but their spines still grew curved as they entered adulthood. This model is typical of the majority of human scoliosis cases, where there are no signs of problems until growth spurts just before or during adolescence. Adolescent idiopathic scoliosis affects 2-4% of all children aged 10 to 16.

Adolescent-onset scoliosis in humans is more common in girls. Interestingly, researchers noticed more of their female fish developed scoliosis than their male fish. The reasons for why females are more susceptible remains a mystery, but it does further support the strength of the using this zebrafish model to study the genetic causes of scoliosis.

Route to Disease

A piece of DNA that regulates LBX1 is mutated, so LBX1 is hyperactive. Excess LBX1 prevents the activity of the wnt5b promoter. An inactive promoter means the gene wnt5b is less active. Insufficient wnt5b means the gene RhoA is not active. This cascade or signaling pathway is the link between LBX1 and scoliosis.

The Wnt/PCP cell signaling pathway is well mapped and already implicated in causing scoliosis, but no one had yet connected LBX1 to Wnt/PCP. The team of researchers designed additional experiments to see how the genes might interact.

The wnt5b gene helps control multiple aspects of cell growth, including regulating how cells become bones and muscles early in development. The spine is an interconnected complex of bones, nerves, and muscles whose formation and growth depends on a series of elaborate genetic regulations. Improper control of wnt5b could partially explain the skeletal irregularities that cause scoliosis.

Detour for Prevention

Researchers decided to test if artificially replacing wnt5b or RhoA could prevent scoliosis and death in fish modeling the congenital version of scoliosis. When the wnt5b or RhoA was added very early in embryonic development, the fish had significantly less severe scoliosis, but the other associated deformities were still fatal. It is unlikely that this method will prevent or correct adolescent scoliosis because of how early the wnt5b or RhoA needed to be provided to have an effect on straightening the spine.

“Greater understanding of the genetic mechanisms that lead to adolescent-onset scoliosis is necessary before any genetic interventions for clinical treatments can be designed,” said Prof. Shukunami.

Never argue with an idiot. They always drag you down to their level, and then they beat you with experience. --Twain
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Surgery 2/10/93 A/P fusion T4-L3
Surgery 1/20/11 A/P fusion L2-sacrum w/pelvic fixation

“A genetic test called the ScoliScore AIS Prognostic Test already exists for adolescents recently diagnosed with scoliosis to predict if the curve of the spine will get worse, which can guide treatment decisions. Studies like ours that identify genes important in causing scoliosis can help further develop this current prognostic test into a clinically predictive genetic test to identify scoliosis before symptoms occur,” said Chisa Shukunami, DDS, PhD, Professor in the Department of Molecular Biology and Biochemistry at Hiroshima University."

Evidently these people didn't get the memo. Scoliscore Failed It's Second, Independent Analysis. Every gene in the Scoliscore test was found to be a false positive by two separate, independent labs. Every. Single. One. False. If you spent money on this test maybe try to get your money back before the share price of the company that owns it, Transgenomic falls to 0. It currently sits at 67 cents.

Don't ask me why I posted this after months of MIA happiness and bliss. After working out with Scott tonight some instinct deep inside told me that I needed to check in.

Multiple very recent studies have connected Scoliosis not to heredity (which makes zero sense if you believe in natural selection) but to problems with Vitamin-D. Check Pubmed for the latest and ask your child's doctor about a Vitamin-D lamp if he/she doesn't spend a significant amount of time outdoors.

Interesting article. They need to do mammalian studies to see if the same holds true.
I'm not so sure about Scoliscore. I am still a strong believer in the genetics of scoliosis because of my family. However, in our case, we've "discovered" that we have an apparent autosomal dominant degenerative neuromuscular disease. My sister is affected and my dad was affected, but neither have/had scoliosis. Whether my grandmother was "affected" or not will remain a mystery as she died at the ripe age of 82 from breast cancer. She had so-called "fibromyalgia" because she was in constant pain (a side effect of this disease) and scoliosis. However, IF she was affected, the progression was VERY slow and didn't shorten her life-span. My dad's life was cut short, but he still made it to 79, the last four years as a quadriplegic. He eventually succumbed to drowning by not having the muscles to cough, typical of MD and ALS patients. We thought it was ALS and the scoliosis was idiopathic. However, when I started having trouble walking and needed a walker at the ripe old age of 45, I knew something else was up and the scoliosis was probably related to the MD (D=disease not dystrophy, the MDA even made the change in terminology) that I have since five out of the seven likely affected have or had, in my son's case, scoliosis (but he does have the vertebral malformation Spina bifida occulta in two vertebrae). Just an FYI, some muscle diseases tend to show up earlier with each generation.

So, whether Scoliscore failed or not, I AM interested in what this researcher found and whether it plays a role in all scoliosis or just IIS, JIS and AIS. It seems that it could apply to ANY spinal deformity, such as different Spina bifidas including occulta, wedged or misshapen vertebrae, or even extra ribs (my daughter has a cervical rib). Mammalian studies would make it easier to make that determination as the vertebrae would be larger to view. I've never seen a Spina bifida in a fish, but have had fish with scoliosis - they seem to die younger. I suppose other fish would eat them before they could be discovered or they would die upon hatching due to paralysis and then get eaten. I raised mice for snake food and found kyphosis in some of them. They also died younger. I took very good care of them so it wasn't due to neglect.

Dingo, not to invalidate your point, vitamin deficiencies most certainly can monkey with biomolecular pathways. It is a well known fact that many people that live far north or south of the equator suffer from vitamin D deficiency. It's also a likely scenario even where you live. I lived in Phx and my dad lived there for decades. I also lived in the Mohave Desert where our thermometer peaked out at 131os one very HOT summer and it was in the shade! People in these hotter climates spend a LOT of time indoors, although with access to water, they can also get their fair share of overexposure to the sun. But it also depends on how the body has the ability to convert sunlight into vitamin D.

There could be numerous vitamin or mineral deficiencies that we have. You may argue that scoliosis goes back millennia and be right. But you have to consider that even those people may not have had a "well balanced" diet as they were limited to what regional food could be found.

Food for thought. It could be passed down genetically from a hereditary standpoint OR it could be a damaged pathway and have a biomolecular cause. It could also be a random mutation that frequently occurs that causes the pathways to be disrupted.

Any way you put it, that was a very interesting paper. Of course, it will have to be studied much further, but at least it seems to a valid starting point.

vitamin deficiencies most certainly can monkey with biomolecular pathways. It is a well known fact that many people that live far north or south of the equator suffer from vitamin D deficiency. It's also a likely scenario even where you live. I lived in Phx and my dad lived there for decades. I also lived in the Mohave Desert where our thermometer peaked out at 131os one very HOT summer and it was in the shade! People in these hotter climates spend a LOT of time indoors, although with access to water, they can also get their fair share of overexposure to the sun. But it also depends on how the body has the ability to convert sunlight into vitamin D.

I believe 5 studies have connected Scoliosis with low levels of Vitamin D. However they haven't determined whether it is a cause or consequence of Scoliosis.

Vitamin D is a subject of growing interest because different groups of scientists in different parts of the world are finding the same thing. Not true for the gene hunters. Every gene in the Scoliscore test was UNfound when independently tested. Twice.

Genetics of Scoliosis is a very hot topic.

Nobody with a scientific understanding of scoliosis research can doubt genetics is an important field of study. For example, at the IMAST conference coming up for July 2016, a genetics paper won the 2015 John H. Moe Award for the Best Basic Science E-Poster at the Annual Meeting & Course.

If you see someone ignorantly claiming genetics is not a hot area of scoliosis research, you know they don't understand the science literature. The ScoliScore situation is not the same as this and other genetic research. You can't just assume it is all the same and lump it together. To a lay person it must all look the same. So whether or not Scoliscore pans out has ZERO to do with this work. But try convincing a lay person that. Good luck.

Lay people don't like genetics because they don't understand it but that has ZERO bearing on what scientists are working on as we can see from the award winners named above.

Last edited by Pooka1; 04-23-2016 at 04:23 PM.

Sharon, mother of identical twin girls with scoliosis

No island of sanity.

Question: What do you call alternative medicine that works?Answer: Medicine

Vitamin D is a subject of growing interest because different groups of scientists in different parts of the world are finding the same thing. Not true for the gene hunters. Every gene in the Scoliscore test was UNfound when independently tested. Twice.

Are you are sure about this conclusion as you were about your other conclusion in re the work in Canada on melatonin and inflammation markers?

Sharon, mother of identical twin girls with scoliosis

No island of sanity.

Question: What do you call alternative medicine that works?Answer: Medicine

The evidence is IN

GENETIC EVIDENCE IN IS

Is IS genetic?

The recognition of genetic influences in IS is well-documented [19-25]. Familial forms of IS were described as early as 1922 [26]. Since then, reports of multiple twin sets and twin series have consistently shown higher concordance in monozygotic (MZ) compared to dizygotic (DZ) twins (reviewed in [27]). A meta-analysis of these clinical twin studies revealed 73% MZ compared to 36% DZ concordances [28]. Interestingly, in this series there was a significant correlation with curve severity in monozygous twins (P<.0002), but not dizygous twins. No correlation with curve pattern was found, suggesting the importance of genetic factors in controlling susceptibility and disease course, but not necessarily disease pattern. More recently, Andersen et al. [29] reported their findings using the Danish Twin Registry. They found 25% proband-wise concordance in monozygotic twins (6 of 44 concordant) compared to 0% concordance (0 of 91) in dizygotic twins, with an overall prevalence of approximately 1%. The lower concordances in both groups as compared with prior results may be explained by differences in study design, specifically, ascertainment in clinics versus by registry, and screening by examination versus questionnaire. Nevertheless the overall trend obtained for all studies suggests strong genetic effects in IS. Interestingly, measured concordances in monozygotic twins were below 100%, reflecting the complexity of disease and suggesting the involvement of as yet unknown environmental or stochastic factors in disease susceptibility.

Gene associated with adolescent idiopathic scoliosis identified

Date: May 12, 2013
Source: RIKEN
Summary: Researchers have identified the first gene to be associated with adolescent idiopathic scoliosis (also called AIS) across Asian and Caucasian populations. The gene is involved in the growth and development of the spine during childhood.

Sharon, mother of identical twin girls with scoliosis

No island of sanity.

Question: What do you call alternative medicine that works?Answer: Medicine

SRS says genetics is an active research field

Note the SRS is still mentioning the ScoliScore test. There is a reason for that.

Genetic Connection

"Idiopathic" means that the condition has no identifiable causes although significant research is ongoing, including the genetic basis for AIS. Approximately 30% of AIS patients have some family history of scoliosis, which would indicate a genetic connection. Many Scoliosis Research Society members are working to identify the genes that cause AIS, and this knowledge contin-ues to expand at a rapid pace. A genetic screening test, called the ScoliScore™, is available as an adjunct to clinical and x-ray information to determine AIS’ risk of progression.

Sharon, mother of identical twin girls with scoliosis

No island of sanity.

Question: What do you call alternative medicine that works?Answer: Medicine

A genetics study from last year

While many genes have been implicated in causing scoliosis, a genetic link between familial cases of the condition has been harder to pin down. Now scientists from the University of Montreal say they have pinpointed the exact gene responsible — the POC5 gene. The team has published their findings in the Journal of Clinical Investigation.

Sharon, mother of identical twin girls with scoliosis

No island of sanity.

Question: What do you call alternative medicine that works?Answer: Medicine

Note the SRS is still mentioning the ScoliScore test. There is a reason for that.

You are quite correct. Not only has the SRS and perhaps other organizations promoted Scoliscore but Transgenomic (a penny stock company) continues to sell it for $2,950 a copy. This despite the fact that every gene it tests for was found to be a false positive. Twice. And no gene it tests for has ever been independently verified. Ever. By anyone.

Make of that what you will.

For no particular reason this study just popped into my head. I have no idea where these thoughts come from.

A detailed review of all 2,047 biomedical and life-science research articles indexed by PubMed as retracted on May 3, 2012 revealed that only 21.3% of retractions were attributable to error. In contrast, 67.4% of retractions were attributable to misconduct, including fraud or suspected fraud

You are quite correct. Not only has the SRS and perhaps other organizations promoted Scoliscore but Transgenomic (a penny stock company) continues to sell it for $2,950 a copy. This despite the fact that every gene it tests for was found to be a false positive. Twice. And no gene it tests for has ever been independently verified. Ever. By anyone.

Make of that what you will.

For no particular reason this study just popped into my head. I have no idea where these thoughts come from.

AbstractPURPOSE: To estimate the heritability of scoliosis in the Swedish Twin Registry.

METHODS: Self-reported data on scoliosis from 64,578 twins in the Swedish Twin Registry were analysed. Prevalence, pair- and probandwise concordances and tetrachoric correlations in mono- and dizygotic same-sex twins were calculated. The relative importance of genetic variance, i.e. the heritability, and unique and shared environmental variance was estimated using structural equation modelling in Mx software. In addition, all twins in the twin registry were matched against the Swedish Inpatient Register on the primary diagnosis idiopathic scoliosis.

RESULTS: The prevalence of scoliosis was 4%. Pair- and probandwise concordance was 0.11/0.17 for mono- and 0.04/0.08 for same-sex dizygotic twins. The tetrachoric correlation (95% CI) was 0.41 (0.33-0.49) in mono- and 0.18 (0.09-0.29) in dizygotic twins. The most favourable model in the Mx analyses estimated the additive genetic effects (95% CI) to 0.38 (0.18-0.46) and the unique environmental effects to 0.62 (0.54-0.70). Shared environmental effects were not significant. The pairwise/probandwise concordance for idiopathic scoliosis in the Swedish Inpatient Register was 0.08/0.15 for monozygotic and zero/zero for same-sex dizygotic twins.

CONCLUSION: Using self-reported data on scoliosis from the Swedish Twin Registry, we estimate that 38% of the variance in the liability to develop scoliosis is due to additive genetic effects and 62% to unique environmental effects. This is the first study of sufficient size to make heritability estimates of scoliosis.